In situ graphene liquid cell-transmission electron microscopy study of insulin secretion in pancreatic islet cells.

Background: Islet cell transplantation is one of the key treatments for type 1 diabetes. Understanding the mechanisms of insulin fusion and exocytosis are of utmost importance for the improvement of the current islet cell transplantation and treatment of diabetes. These phenomena have not been fully evaluated due either to the lack of proper dynamic imaging, or the lack of proper cell preservation during imaging at nanoscales.

Syntaxin 4 Expression in Pancreatic β-Cells Promotes Islet Function and Protects Functional β-Cell Mass.

Syntaxin 4 (Stx4) enrichment in human and mouse islet grafts improves the success of transplants in reversing streptozotocin (STZ)-induced diabetes in mice, although the underlying molecular mechanisms remain elusive. Toward a further understanding of this, human islets and inducible transgenic mice that selectively overexpress Stx4 in islet β-cells (βTG-Stx4) were challenged with proinflammatory stressors in vitro and in vivo. Remarkably, βTG-Stx4 mice resisted the loss of β-cell mass and the glucose intolerance that multiple low doses of STZ induce.

Pancreatic β-cell regeneration: advances in understanding the genes and signaling pathways involved.

Recent advances in β-cell regeneration in vivo are providing insights into the mechanisms involved in the conversion of distinct pancreatic cell lineages into β cells. These mechanisms mostly involve reactivation of the gene encoding the pancreatic endocrine cell-specifying transcription factor neurogenin-3.

Pancreatic β-cell regeneration: Facultative or dedicated progenitors?

The adult pancreas is only capable of limited regeneration. Unlike highly regenerative tissues such as the skin, intestinal crypts and hematopoietic system, no dedicated adult stem cells or stem cell niche have so far been identified within the adult pancreas. New β cells have been shown to form in the adult pancreas, in response to high physiological demand or experimental β-cell ablation, mostly by replication of existing β cells.

Xeno-Transplantation of macro-encapsulated islets and Pluripotent Stem Cell-Derived Pancreatic Progenitors without Immunosuppression.

Islet transplantation effectively treats diabetes but relies on immune suppression and is practically limited by the number of cadaveric islets available. An alternative cellular source is insulin-producing cells derived from pluripotent cell sources. Three animal cohorts were used in the current study to evaluate whether an oxygen-providing macro-encapsulation device, 'βAIR', could function in conjunction with human embryonic stem cells (hESCs) and their derivatives.

Wnt7b is required for epithelial progenitor growth and operates during epithelial-to-mesenchymal signaling in pancreatic development.

Wnt signaling is a well conserved pathway critical for growth, patterning and differentiation of multiple tissues and organs. Previous studies on Wnt signaling in the pancreas have been based predominantly on downstream pathway effector genes such as β-catenin. We here provide evidence that the canonical-pathway member Wnt7b is a physiological regulator of pancreatic progenitor cell growth.

Notch signaling in the pancreas: patterning and cell fate specification.

Notch signaling is an evolutionarily conserved mechanism adapted to control binary fate decisions. The first evidence of Notch in pancreatic development focused on its critical role in controlling endocrine fate decisions. Since then, we have come to understand that this signaling system operates iteratively in the pancreas, and is not limited to the control of endocrine fate decision.

A far-upstream (-70 kb) enhancer mediates Sox9 auto-regulation in somatic tissues during development and adult regeneration.

SOX9 encodes a transcription factor that presides over the specification and differentiation of numerous progenitor and differentiated cell types, and although SOX9 haploinsufficiency and overexpression cause severe diseases in humans, including campomelic dysplasia, sex reversal and cancer, the mechanisms underlying SOX9 transcription remain largely unsolved. We identify here an evolutionarily conserved enhancer located 70-kb upstream of mouse Sox9 and call it SOM because it specifically activates a Sox9 promoter reporter in most Sox9-expressing somatic tissues in transgenic mice. Moreover, SOM-null fetuses and pups reduce Sox9 expression by 18-37% in the pancreas, lung, kidney, salivary gland, gut and liver.

Notch-mediated post-translational control of Ngn3 protein stability regulates pancreatic patterning and cell fate commitment.

Ngn3 is recognized as a regulator of pancreatic endocrine formation, and Notch signaling as an important negative regulator Ngn3 gene expression. By conditionally controlling expression of Ngn3 in the pancreas, we find that these two signaling components are dynamically linked. This connection involves transcriptional repression as previously shown, but also incorporates a novel post-translational mechanism.

SEC23B is required for the maintenance of murine professional secretory tissues.

In eukaryotic cells, newly synthesized secretory proteins require COPII (coat protein complex II) to exit the endoplasmic reticulum (ER). COPII contains five core components: SAR1, SEC23, SEC24, SEC13, and SEC31. SEC23 is a GTPase-activating protein that activates the SAR1 GTPase and also plays a role in cargo recognition.

Exocrine ontogenies: on the development of pancreatic acinar, ductal and centroacinar cells.

This review summarizes our current understanding of exocrine pancreas development, including the formation of acinar, ductal and centroacinar cells. We discuss the transcription factors associated with various stages of exocrine differentiation, from multipotent progenitor cells to fully differentiated acinar and ductal cells. Within the branching epithelial tree of the embryonic pancreas, this involves the progressive restriction of multipotent pancreatic progenitor cells to either a central "trunk" domain giving rise to the islet and ductal lineages, or a peripheral "tip" domain giving rise to acinar cells.

Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells.

Early pancreatic morphogenesis is characterized by the transformation of an uncommitted pool of pancreatic progenitor cells into a branched pancreatic epithelium that consists of 'tip' and 'trunk' domains. These domains have distinct molecular signatures and differentiate into distinct pancreatic cell lineages. Cells at the branched tips of the epithelium develop into acinar cells, whereas cells in the trunk subcompartment differentiate into endocrine and duct cells.

Ptf1a triggers GABAergic neuronal cell fates in the retina.

Background: In recent years, considerable knowledge has been gained on the molecular mechanisms underlying retinal cell fate specification. However, hitherto studies focused primarily on the six major retinal cell classes (five types of neurons of one type of glial cell), and paid little attention to the specification of different neuronal subtypes within the same cell class. In particular, the molecular machinery governing the specification of the two most abundant neurotransmitter phenotypes in the retina, GABAergic and glutamatergic, is largely unknown.

Combined ectopic expression of Pdx1 and Ptf1a/p48 results in the stable conversion of posterior endoderm into endocrine and exocrine pancreatic tissue.

Patterning of the embryonic endoderm into distinct sets of precursor cells involves the precisely regulated activities of key transcription regulators. Ectopic, pan-endodermal activation of XPtf1a/p48 during pancreas precursor cell stages of Xenopus embryogenesis results in an expansion of the pancreatic territory, precisely within the borders of XlHbox8 expression. A combination of both activities is sufficient to expand the pancreatic precursor cell population also into more posterior portions of the endoderm.

Retinoic acid signaling is essential for pancreas development and promotes endocrine at the expense of exocrine cell differentiation in Xenopus.

How and when the vertebrate endoderm is first subdivided into discrete progenitor cell populations that will give rise to the different major organs, including pancreas and liver, are only poorly understood. We have used Xenopus laevis as a model system to characterize these events, since it is particularly suited to study the early embryonic patterning in vertebrates. Our experimental results support the notion that retinoic acid (RA) functions as an essential endodermal patterning signal in Xenopus and that it acts as early as during gastrulation.

Pancreatic protein disulfide isomerase (XPDIp) is an early marker for the exocrine lineage of the developing pancreas in Xenopus laevis embryos.

The pancreas develops from dorsal and ventral epithelial extensions at the foregut/midgut boundary in Xenopus embryos. Endocrine and exocrine specification is thought to occur from a pool of uniform precursor cells. While the genetic network controlling endocrine specification and differentiation has been the object of extensive investigations, the corresponding mechanism leading to the exocrine pancreas is much less understood.